Drug Discovery Research Articles

Ginsenoside Rg1 mitigates cerebral ischaemia/reperfusion injury in mice by inhibiting autophagy through activation of mTOR signalling.

Reperfusion injury, which is distinct from ischaemic injury, occurs when blood flow is restored in previously ischaemic brain tissue, further compromising neurons and other cells and worsening the injury. There is currently a lack of pharmaceutical agents and therapeutic interventions that specifically mitigate cerebral ischaemia/reperfusion (I/R) injury. Ginsenoside Rg1 (Rg1), a protopanaxatriol-type saponin isolated from Panax ginseng C. A. Meyer, has been found to protect against cerebral I/R injury, but its intricate protective mechanisms remain to be elucidated. Numerous studies have shown that autophagy plays a crucial role in protecting brain tissue during the I/R process and is emerging as a promising therapeutic strategy for effective treatment. In this study, we investigated whether Rg1 protected against I/R damage in vitro and in vivo by regulating autophagy. Both MCAO and OGD/R models were established. SK-N-AS and SH-SY5Y cells were subjected to OGD followed by reperfusion with Rg1 (4-32 μM). MCAO mice were injected with Rg1 (30 mg·kg-1·d-1. i.p.) for 3 days before and on the day of surgery. Rg1 treatment significantly mitigated ischaemia/reperfusion injury both in vitro and in vivo. Furthermore, we demonstrated that the induction of autophagy contributed to I/R injury, which was effectively inhibited by Rg1 in both in vitro and in vivo models of cerebral I/R injury. Rg1 inhibited autophagy through multiple steps, including impeding autophagy initiation, inducing lysosomal dysfunction and inhibiting cathepsin enzyme activities. We revealed that mTOR activation was pivotal in mediating the inhibitory effect of Rg1 on autophagy. Treatment with Torin-1, an autophagy inducer and mTOR-specific inhibitor, significantly reversed the impact of Rg1 on autophagy, decreasing its protective efficacy against I/R injury both in vitro and in vivo. In conclusion, our results suggest that Rg1 may serve as a promising drug candidate against cerebral I/R injury by inhibiting autophagy through activation of mTOR signalling.

Discovery of the Aminated Quinoxalines as Potential Active Molecules

Background: In recent years, as the biological activity of the quinoxaline skeleton has been revealed in numerous studies, interest in synthesizing new prototype molecules for the treatment of many chronic diseases, especially cancer, has increased. Methods: The desired alkoxy substituted aminoquinoxalines (AQNX1-9) were synthesized by the reaction of QNX and alkoxy substituted aryl amines such as 2-methoxyaniline, 4-methoxyaniline, 2- ethoxyaniline, 3-ethoxyaniline, 4-ethoxyaniline, 4-butoxyaniline, 2,4-dimethoxyaniline, 3,4- dimethoxyaniline, and 3,5-dimethoxyaniline according to the previously published procedure. QNX was aminated in DMSO at 130°C. We synthesized various alkoxy-substituted aminoquinoxaline compounds (AQNX1-9) and evaluated their anticancer and antimicrobial activities in order to expand the search to related structures. In particular, two aminoquinoxaline (AQNX5 and AQNX6) compounds, coded as NSC D-835971/1 and NSC D-835972/1 by the National Cancer Institute in the USA, were screened for anticancer screening at a dose of 10-5 M on a full panel of 60 human cell lines obtained from nine human cancer cell types (leukemia, melanoma, non-small cell lung, colon, central (nervous system, ovarian, kidney, prostate, and breast cancer). Results: Further in silico studies were also conducted for the compound AQNX5 (NSC D- 835971/1), which was found to be the most active antiproliferative agent, especially against leukemia cell lines. Molecular docking studies showed that AQNX5 interacted with Glu286 and Lys271 through hydrogen bonding and π-stacking interaction in the ATP binding region of Abl kinase, which is indicated as a potential target of leukemia. Besides, AQNX5 occupied the minor groove of the double helix of DNA via π-stacking interaction with DG-6. Conclusion: According to in silico pharmacokinetic determination, AQNX5 was endowed with drug-like properties as a potential anticancer drug candidate for future experiments. In the light of these findings, more research will focus on aminated quinoxalines' ability to precisely target leukemia cancer cell lines.

β-Arbutin and cisplatin: A combined approach to modulating apoptosis, cell viability, and migration in bladder cancer cells

One of the preferred treatments for bladder cancer, one of the most common cancers worldwide, is cisplatin-based chemotherapy. Since most tumor cells show cisplatin resistance, it is very important to discover new agents without adverse side effects. β-arbutin, a hydroquinone-β-D-glucopyranoside, has biological properties such as antioxidant, antimicrobial, anti-inflammatory, and anticancer, and is a phytochemical widely used as a skin whitener. In this study, β-arbutin was purified from the animal feed plant Onobrychis buhseana Boiss. (sainfoin). The study aimed to investigate the combined effects of cisplatin, a clinically used chemotherapeutic agent, and β-arbutin on HT-1376 bladder cancer cells for apoptosis, cell viability, and migration. In the study, after HT-1376 bladder cancer cells were cultured, optimum β-arbutin and cisplatin doses were determined on HT-1376 cells using the WST-1 test. To determine the apoptotic and migratory effects, flow cytometry and wound healing assays were performed. In HT-1376 cells, β-Arbutin led to greater apoptotoic and migratory effects when used alone and combined with Cisplatin (p < 0.0001 for apoptotic and migratory effects treated with β-Arbutin alone, p < 0.0001 for apoptotic and migratory effects when combined with Cisplatin). As a result, it can be suggested that β-arbutin may be a good drug candidate for treating bladder cancer.

Deciphering the Underlying Mechanisms of Sanleng-Ezhu for the Treatment of Idiopathic Pulmonary Fibrosis Based on Network Pharmacology and Single-cell RNA Sequencing Data.

To decipher the underlying mechanisms of Sanleng-Ezhu for the treatment of idiopathic pulmonary fibrosis based on network pharmacology and single-cell RNA sequencing data. Idiopathic Pulmonary Fibrosis (IPF) is the most common type of interstitial lung disease. Although the combination of herbs Sanleng (SL) and Ezhu (EZ) has shown reliable efficacy in the management of IPF, its underlying mechanisms remain unknown. Based on LC-MS/MS analysis and the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database, we identified the bioactive components of SL-EZ. After obtaining the IPF-related dataset GSE53845 from the Gene Expression Omnibus (GEO) database, we performed the differential expression analysis and the weighted gene co-expression network analysis (WGCNA), respectively. We obtained lowly and highly expressed IPF subtype gene sets by comparing Differentially Expressed Genes (DEGs) with the most significantly negatively and positively related IPF modules in WGCNA. Subsequently, we performed Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses on IPF subtype gene sets. The low- and highexpression MCODE subgroup feature genes were identified by the MCODE plug-in and were adopted for Disease Ontology (DO), GO, and KEGG enrichment analyses. Next, we performed the immune cell infiltration analysis of the MCODE subgroup feature genes. Single-cell RNA sequencing analysis demonstrated the cell types which expressed different MCODE subgroup feature genes. Molecular docking and animal experiments validated the effectiveness of SL-EZ in delaying the progression of pulmonary fibrosis. We obtained 5 bioactive components of SL-EZ as well as their corresponding 66 candidate targets. After normalizing the samples of the GSE53845 dataset from the GEO database source, we obtained 1907 DEGs of IPF. Next, we performed a WGCNA analysis on the dataset and got 11 modules. Notably, we obtained 2 IPF subgroups by contrasting the most significantly up- and down-regulated modular genes in IPF with DEGs, respectively. The different IPF subgroups were compared with drugcandidate targets to obtain direct targets of action. After constructing the protein interaction networks between IPF subgroup genes and drug candidate targets, we applied the MCODE plug-in to filter the highest-scoring MCODE components. DO, GO, and KEGG enrichment analyses were applied to drug targets, IPF subgroup genes, and MCODE component signature genes. In addition, we downloaded the single-cell dataset GSE157376 from the GEO database. By performing quality control and dimensionality reduction, we clustered the scattered primary sample cells into 11 clusters and annotated them into 2 cell subtypes. Drug sensitivity analysis suggested that SL-EZ acts on different cell subtypes in IPF subgroups. Molecular docking revealed the mode of interaction between targets and their corresponding components. Animal experiments confirmed the efficacy of SL-EZ. We found SL-EZ acted on epithelial cells mainly through the calcium signaling pathway in the lowly-expressed IPF subtype, while in the highly-expressed IPF subtype, SL-EZ acted on smooth muscle cells mainly through the viral infection, apoptosis, and p53 signaling pathway.

High potency 3-carboxy-2-methylbenzofuran pendrin inhibitors as novel diuretics

Pendrin (SLC26A4) is an anion exchanger expressed in epithelial cells of kidney and lung. Pendrin inhibition is a potential treatment approach for edema, hypertension and inflammatory lung diseases. We have previously identified first-in-class pendrin inhibitors by high-throughput screening, albeit with low potency for pendrin inhibition (IC50 ∼10 μM). Here, we performed a de novo small molecule screen with follow-on structure-activity studies to identify more potent pendrin inhibitors. Screening of 50,000 synthetic small molecules identified four novel classes of pendrin inhibitors with diverse scaffolds, including 5-benzyloxy-2-methylbenzofurans, N-aryl urea substituted 5-methyltryptamines, N-aryl urea substituted anthranilic acid, and substituted N-benzyl 3-carboxyindoles. The most potent inhibitor from the initial screen, a 3-carboxy-2-methylbenzofuran (1a), had IC50 of 4.1 μM. Structure-activity studies using 732 benzofuran analogs identified 1d with IC50 ∼ 0.5 μM for pendrin inhibition. Selectivity studies showed that 1d has minimal or no activity against related ion channels/transporters including SLC26A3, SLC26A6, SLC26A9 and CFTR at high concentrations. 1d administration to mice at 10 mg/kg had no effect on urine volume when used alone, but potentiated the diuretic effect of furosemide by 45%. In conclusion, we have identified novel pendrin inhibitors with greatly improved potency and good in vivo efficacy. These compounds can be used as pharmacological tools to study the roles of pendrin, and potentially developed as drug candidates for edema, hypertension and lung diseases.

Importance of tailored non-clinical safety testing of novel antimalarial drugs: Industry best-practice

Malaria is an acute, debilitating parasitic illness. There were 249 million cases of malaria in 2022, resulting in 608,000 deaths globally, 76% of which were children ≤5 years. The unique nature of this disease (recurrences leading to re-treatments and numerous organ systems affected), specific clinical treatment regimens, poor compliance, and diversity of affected populations (predominantly pediatrics, women of childbearing potential, pregnant and lactating women), often makes standard testing approaches inadequate, and tailor-made safety assessments are more appropriate.We provide best practice recommendations based on company experience for the non-clinical safety assessment of antimalarial drugs, with a focus on small molecules since they represent the majority of drug candidates for this illness. We focus on specific testing considerations for repeat dose toxicity studies, including combination toxicity assessments, since new drug treatment regimens typically foresee short treatment durations to improve compliance (i.e., 1 day) with combinations of compounds to improve efficacy and limit potential resistance. Due to the target population, the timing of reproductive, developmental, and juvenile toxicity studies may be earlier than general testing roadmaps for other small molecule drugs.In conclusion, key recommendations presented should enable a more effective and efficient development path whilst protecting clinical trial participants and patients.

Antiphytopathogenic Diphenyl Ethers from the Marine-derived Fungus Aspergillus sydowii

Background: Natural products from the marine-derived Aspergillus sp. have great potential in agricultural usage due to their broad biological activities. Objective: This study was designed to investigate the antiphytopathogenic compounds from marinederived fungus Aspergillus sydowii LW09. Methods: The compounds were isolated and purified by chromatography methods, and their structures were elucidated by analysis of the NMR and MS spectroscopic data as well as comparison with those of literature. All compounds were evaluated for antibacterial activities against phytopathogenic bacteria Pseudomonas syringae and Ralstonia solanacarum, along with spore germination inhibition of phytopathogenic fungi Fusarium oxysporum and Alternaria alternata. Results: Two diphenyl ethers violaceols I (1) and II (2), along with two alkaloids acremolin (3) and WIN 64821 (4) were isolated from the fermentation extracts of A. sydowii LW09. Compound 1 showed significant antibacterial activity against P. syringae and R. solanacarum with the same MIC values of 4 μg/mL, while compound 2 showed obvious antibacterial activity against P. syringae and R. solanacarum with MIC values of 2 and 1 μg/mL, respectively. Moreover, both 1 and 2 could inhibit the spore germination of F. oxysporum in the concentration range of 64–128 μg/mL. In addition, violaceol I (1) also inhibited the spore germination of A. alternata at 128 μg/mL. Conclusion: This study provided the potential antiphytopathogenic drug candidate for further studies.

A Review on Tau Targeting Biomimetics Nano Formulations: Novel Approach for Targeting Alzheimer's Diseases.

Central nervous system disorders are prevalent, profoundly debilitating, and poorly managed. Developing innovative treatments for these conditions, including Alzheimer's disease, could significantly improve patients' quality of life and reduce the future economic burden on healthcare systems. However, groundbreaking drugs for central nervous system disorders have been scarce in recent years, highlighting the pressing need for advancements in this field. One significant challenge in the realm of nanotherapeutics is ensuring the precise delivery of drugs to their intended targets due to the complex nature of Alzheimer's disease. Although numerous therapeutic approaches for Alzheimer's have been explored, most drug candidates targeting amyloid-β have failed in clinical trials. Recent research has revealed that tau pathology can occur independently of amyloid-β and is closely correlated with the clinical progression of Alzheimer's symptoms. This discovery suggests that tau could be a promising therapeutic target. One viable approach to managing central nervous system disorders is the administration of nanoparticles to neurons, intending to inhibit tau aggregation by directly targeting p-tau. In Alzheimer's disease, beta-amyloid plaques and neurofibrillary tau tangles hinder neuron transmission and function. The disease also triggers persistent inflammation, compromises the blood-brain barrier, leads to brain shrinkage, and causes neuronal loss. While current medications primarily manage symptoms and slow cognitive decline, there is no cure for Alzheimer's.

Discovery of the synergy between sulindac and NO expands the application of NSAIDs in cardiac complications

Cardiac inflammation, a pathological cornerstone in cardiac dysfunction, triggers diastolic impairment, leading to profound myocardial hypoxia. This hypoxic state serves as a potent stimulus for the amplification of inflammatory mediator release, ultimately limiting the therapeutic potential of monotherapies. To address this challenge, compounds that integrate non-steroidal anti-inflammatory drugs (NSAIDs) with nitric oxide (NO) donors was synthesized. The in vitro screening unveiled the remarkable anti-hypoxic inflammatory injury activity of a sulindac derivative, despite its suboptimal COX-2 inhibition when comparing with other NSAIDs derivatives. This revelation propelled us to delve deeper into the intricate synergistic relationship between sulindac and NO. Employing two-way ANOVA and high-throughput screening technique, we incontrovertibly confirmed their synergism. Further, the underlying mechanism was unmasked through the detection of signal molecule release levels and western blot analysis. In a definitive step, we evaluated the therapeutic effects of sulindac and its derivatives in vivo, leveraging a rat model that recapitulates cardiac inflammation coupled with hypoxia. Our findings herald a promising drug candidate and establish a foundation for the expanded utilization of NSAIDs in the intricate landscape of cardiovascular diseases.

Molecular Docking, Pharmacophore Mapping, and Virtual Screening of Novel Glucokinase Activators as Antidiabetic Agents

Background: A pivotal impetus has led to the development of numerous small molecules to develop therapeutic strategies for type 2 diabetes. Novel heterocyclic derivatives are now available with expansive pharmacological activity designed specifically to activate Glucokinase (GK) in the body. This target is of particular significance in antidiabetic drug design since it is a newly validated target. Individuals with type 2 diabetes are unable to maintain blood glucose homeostasis due to impaired glucokinase function. The novel approach to managing type 2 diabetes relies on utilizing heterocyclic derivatives to activate the GK enzyme, also known as a metabolic enzyme. Objective: In this research endeavor, the primary objective was to improve drug delivery while minimizing adverse effects by using molecules that activate glucokinase. Methods: There are 53,000 compounds included in Maybridge's online repository, which has been subjected to rigorous scrutiny. Eight two compounds that encompass the specific oxadiazole core were selectively extracted from this extensive collection. ChemBioDraw Ultra was used for structural drawing, and AutoDock Vina 1.5.6 was used to perform docking analysis. For the online prediction of log P, the SwissADME algorithm was employed. A PKCSM software program was used to predict toxicity for leading compounds. Results: Among all of the compounds, AD80 and AD27 displayed the highest affinity for GK receptors. These compounds, by adhering to Lipinski’s Rule of Five, exhibited good absorption and excretion profiles through the gastrointestinal (GI) tract. Lipinski’s Rule of Five refers to physicochemical properties that favor good oral bioavailability, and these specifications are zero to five hydrogen bond donors, zero to ten hydrogen bond acceptors, molecular weight below 500, and log P no more than five. These criteria ensure that the compounds of the invention have acceptable solubility and permeability, which are vital prerequisites when given orally, to be absorbed via the gastrointestinal wall, metabolized, and found in the urine. Therefore, the chance of drug candidates exhibiting favorable pharmacokinetic characteristics is increased, enhancing their chances of being developed for oral administration. In comparison with standard drugs Dorzagliatin as a glucokinase activator (GKA) and MRK (co-crystallized ligand), these compounds exhibit no skin sensitization, AMES toxicity, or hepatotoxicity. Conclusion: The recently designed lead molecules exhibit an improved pharmacokinetic profile, enhanced binding affinity, and minimal toxicity based on the computational study, potentially making them suitable candidates for further optimization as glucokinase activators.

PANoptosis Signaling Enables Broad Immune Response in Psoriasis: From Pathogenesis to New Therapeutic Strategies

BackgroundAccumulating evidence suggests that regulated cell death, such as pyroptosis, apoptosis, and necroptosis, is deeply involved in the pathogenesis of psoriasis. As a newly recognized form of systematic cell death, PANoptosis is involved in a variety of inflammatory disorders through amplifying inflammatory and immune cascades, but its role in psoriasis remains elusive. ObjectivesTo reveal the role of PANoptosis in psoriasis for a potential therapeutic strategy. MethodsMultitranscriptomic analysis and experimental validation were used to identify PANoptosis signaling in psoriasis. RNA-seq and scRNA-seq analyses were performed to establish a PANoptosis-mediated immune response in psoriasis, which revealed hub genes through WGCNA and predicted disulfiram as a potential drug. The effect and mechanism of disulfiram were verified in imiquimod (IMQ)-induced psoriasis. ResultsHere, we found a highlighted PANoptosis signature in psoriasis patients through multitranscriptomic analysis and experimental validation. Based on this, two distinct PANoptosis patterns (non/high) were identified, which were the options for clinical classification. The high-PANoptosis-related group had a higher response rate to immune cell infiltration (such as M1 macrophages and keratinocytes). Subsequently, WGCNA showed the hub genes (e.g., S100A12, CYCS, NOD2, STAT1, HSPA4, AIM2, MAPK7), which were significantly associated with clinical phenotype, PANoptosis signature, and identified immune response in psoriasis. Finally, we explored disulfiram (DSF) as a candidate drug for psoriasis through network pharmacology, which ameliorated IMQ-mediated psoriatic symptoms through antipyroptosis-mediated inflammation and enhanced apoptotic progression. By analyzing the specific ligandreceptor interaction pairs within and between cell lineages, we speculated that DSF might exert its effects by targeting keratinocytes directly or targeting M1 macrophages to downregulate the proliferation of keratinocytes. ConclusionsPANoptosis with its mediated immune cell infiltration provides a roadmap for research on the pathogenesis and therapeutic strategies of psoriasis.

Combining supervised and unsupervised analyses to quantify behavioral phenotypes and validate therapeutic efficacy in a triple transgenic mouse model of Alzheimer's disease

Behavioral testing is an essential tool for evaluating cognitive function and dysfunction in preclinical research models. This is of special importance in the study of neurological disorders such as Alzheimer’s disease. However, the reproducibility of classic behavioral assays is frequently compromised by interstudy variation, leading to ambiguous conclusions about the behavioral markers characterizing the disease. Here, we identify age- and genotype-driven differences between 3xTg-AD and non-transgenic control mice using a low-cost, highly customizable behavioral assay that requires little human intervention. Through behavioral phenotyping combining both supervised and unsupervised behavioral classification methods, we are able to validate the preventative effects of the immunosuppressant cyclosporine A in a rodent model of Alzheimer’s disease, as well as the partially ameliorating effects of candidate drugs nebivolol and cabozantinib.

Cytotoxic, Antioxidant, and Anti-Genotoxic Properties of Combretastatin A4 in Human Peripheral Blood Mononuclear Cells: A Comprehensive In Vitro Study

Despite significant advances in drug discovery and the promising antitumor potential of combretastatin A4 (CA-4), which selectively targets rapidly dividing cancer cells, CA-4’s effects on non-dividing human cells, such as peripheral blood mononuclear cells (PBMCs), remain unclear. The aim of this study is to evaluate the in vitro bioactivity of CA-4 in human PBMCs, focusing on its antigenotoxic and antioxidant properties, while comparing its cytotoxic potency against PBMCs, cancer cell lines (JAR and HeLa), and the normal trophoblast cell line HTR-8/SVneo. Cell viability and metabolic activity were evaluated using the MTT assay. ROS production in PBMCs was measured using the H2DCFDA assay, and DNA damage was assessed using the Comet assay. CA-4 showed cytotoxicity in PBMCs and HTR-8/SVneo cells at concentrations above 200 µM, while cancer cells, JAR and HeLa, showed cytotoxicity at 100 µM and 1 µM, respectively. CA-4 also reduced ROS levels in PBMCs under oxidative stress and showed antioxidant effects at concentrations from 1 to 200 µM. In addition, CA-4 showed antigenotoxic effects against H2O2-induced DNA damage in PBMCs at concentrations of up to 1 µM. CA-4 exhibited lower cytotoxicity in human PBMCs compared to cancer cells, inhibited ROS production, and showed antioxidant and antigenotoxic properties, providing insight into its potential therapeutic efficacy and safety.

Advancements in benzotriazole derivatives: from synthesis to pharmacological applications

Benzotriazole derivatives have emerged as significant compounds in medicinal chemistry due to their diverse pharmacological activities and unique structural properties. This review discusses the various synthetic strategies employed to develop these derivatives, including solvent-free techniques for N-alkylation and the synthesis of N-acyl benzotriazoles. Characterization methods such as infrared (IR) and nuclear magnetic resonance (NMR) spectroscopy confirm the successful formation of metal-benzotriazole complexes. The pharmacological profiles of benzotriazole derivatives reveal their potential as antimicrobial agents, particularly against Gram-positive and Gram-negative bacteria, including methicillin-resistant Staphylococcus aureus. Additionally, some derivatives exhibit potent antiprotozoal activity against Acanthamoeba castellanii, as well as analgesic effects that surpass those of standard drugs. Antioxidant studies highlight superior free radical scavenging abilities in certain benzotriazole-substituted compounds, while anti-inflammatory derivatives demonstrate activity comparable to common anti-inflammatory medications. Furthermore, significant antifungal activity against Candida albicans and Aspergillus niger positions these compounds as promising alternatives in addressing prevalent health challenges. The findings underscore the importance of benzotriazole derivatives in drug discovery and their potential in combating issues such as antibiotic resistance and oxidative stress.

Machine learning in personalized cancer treatment: Implications for global public health

Cancer remains a leading cause of mortality worldwide, posing a significant challenge to global public health. Traditional approaches to cancer treatment often adopt a "one-size-fits-all" strategy, which may not be effective for every patient due to the complex and heterogeneous nature of the disease. Personalized cancer treatment aims to tailor therapeutic interventions to the individual characteristics of each patient, enhancing the efficacy and reducing adverse effects. In recent years, machine learning (ML) has emerged as a powerful tool in personalized cancer care, offering the potential to revolutionize diagnosis, prognosis, and treatment by leveraging vast amounts of biomedical data. This review explores the current landscape of machine learning applications in personalized cancer treatment, including its role in imaging, genomics, and drug discovery. We provide an overview of key machine learning techniques, highlight successful case studies from both developed and developing nations, and examine the challenges and limitations associated with the integration of these technologies into clinical practice. Furthermore, we discuss the implications of machine learning-driven personalized cancer care for global public health, emphasizing its potential to address disparities in access to healthcare and improve outcomes in resource-limited settings. Finally, we offer insights into future research directions and policy considerations that could accelerate the adoption of machine learning in global cancer treatment, fostering a more equitable and effective healthcare ecosystem.'

Entropy Driven Binding of 2-(4-Aminophenyl)benzothiazole with DNA: An Experimental and Theoretical Insights

Molecular recognition driven by molecular interactions is an intricate part of drug discovery and targeted drug delivery systems due to the dependence of thetherapeutic properties of drugs on interaction with desired target biomolecules as receptors. 2-(4-Aminophenyl) benzothiazole (APB), a heterocyclic molecule containing a benzothiazole nucleus, is known to induce apoptosis besides inhibiting cancer cell development and has been found effective against different microorganisms. This study highlights the spectroscopic and theoretical investigation of binding interactions of APB and ct-DNA. The UV-vis experiments indicate a binding constant of 9.73 ± 0.4 × 105 M-1. The measured binding constants of 1.0 ± 0.2 × 105, 2.4 ± 0.3 × 105 and 3.5 ± 0.3 × 105 at 298, 303 and 308 K, respectively, from fluorescence experiments indicated a dynamic quenching type. The binding was driven by hydrophobic forces with positive ΔHº (64.8467 ± 2 KJ mol–1) and ΔSº (317.12 ± 2 J mol–1 K–1) values besides spontaneity of the process with negative ΔGº values. The binding of APB molecule in the minor groove of ct-DNA was demonstrated by DNA melting tests, viscosity measurements and site marker displacement using ethidium bromide and Hoechst. Additional studies conducted by KI provided support for minor groove binding and NaCl has no impact on the binding electrostatic interactions, while the CD investigations showed no DNA structural alterations. Molecular docking studies also confirmed the experimental findings placing APB in the ct-DNA minor groove.

A deep learning model based on the BERT pre-trained model to predict the antiproliferative activity of anti-cancer chemical compounds

ABSTRACT Identifying new compounds with minimal side effects to enhance patients’ quality of life is the ultimate goal of drug discovery. Due to the expensive and time-consuming nature of experimental investigations and the scarcity of data in traditional QSAR studies, deep transfer learning models, such as the BERT model, have recently been suggested. This study evaluated the model’s performance in predicting the anti-proliferative activity of five cancer cell lines (HeLa, MCF7, MDA-MB231, PC3, and MDA-MB) using over 3,000 synthesized molecules from PubChem. The results indicated that the model could predict the class of designed small molecules with acceptable accuracy for most cell lines, except for PC3 and MDA-MB. The model’s performance was further tested on an in-house dataset of approximately 25 small molecules per cell line, based on IC50 values. The model accurately predicted the biological activity class for HeLa with an accuracy of 0.77 ± 0.4 and demonstrated acceptable performance for MCF7 and MDA-MB231, with accuracy between 0.56 and 0.66. However, the results were less reliable for PC3 and HepG2. In conclusion, the ChemBERTa fine-tuned model shows potential for predicting outcomes on in-house datasets.

Generative adversarial network (GAN) model-based design of potent SARS-CoV-2 Mpro inhibitors using the electron density of ligands and 3D binding pockets: insights from molecular docking, dynamics simulation, and MM-GBSA analysis.

Deep learning-based generative adversarial network (GAN) frameworks have recently been developed to expedite the drug discovery process. These models generate novel molecules from scratch and validate them through molecular docking simulation to identify the most promising candidates for a given drug target. In this study, the SARS-CoV-2 main protease (Mpro) was selected as the drug target. Two distinct GAN algorithms were employed to generate novel small molecules. One approach utilized experimental electron density (ED-based) data of ligands for training to generate drug-like molecules, while the second approach leveraged the target binding pocket to capture spatial and bonding relationship between atoms within the binding pockets. The ED-based approach generated approximately 26,000 molecules, whereas the binding pocket-based method produced around 100 molecules. These generated molecules were subsequently ranked based on molecular docking results using the glide XP score (both flexible and rigid docking) and AutoDock Vina. To identify the most potent GAN-derived molecules, molecular docking was also performed on co-crystallized inhibitor molecules of Mpro. The six most promising molecules from these GAN approaches were further evaluated for stability, interactions, and MM-GBSA binding free energy through molecular dynamics simulations. This analysis led to the identification of four potent Mpro inhibitor molecules, all featuring a 2-benzyl-6-bromophenol scaffold. The binding free energies of these compounds were compared with those of other Mpro inhibitors, revealing that our compounds demonstrated better affinity for Mpro than some broad-spectrum protease inhibitors. The dynamic cross-correlation matrix plot indicated strongly correlated and anti-correlated regions, potentially linked to ligand binding.

Exploring potential natural plant-based antifungal agents in Sri Lanka: A comprehensive review

Recent advances in antifungal drug discovery have prompted a closer inspection of the biology of fungi and the ways in which they adapt to their growing environment. Understanding these findings presents a challenge: developing antifungal agents that can withstand resistance from fungi and effectively combat it. The use of plant-based antifungal agents is gaining momentum within the antifungal drug industry. This review aims to examine the potential to propel current findings on the antifungal activity of selected medicinal plant extracts found in Sri Lanka towards their potential candidacy as novel antifungals. The benefits and adverse effects of fungi are discussed, along with an overview of synthetic and natural antifungal agents. It delves into the modes of action of antifungal agents and the ways in which they encounter resistance from fungi. The review also highlights the classes of phytochemicals in these plant extracts and the mechanisms through which they exhibit antifungal abilities. Furthermore, it summarizes the capability of natural antifungal agents to enhance the antifungal activity of synthetic antifungal drugs through possible synergistic actions. Finally, the barriers to bringing these plant-based antifungal agents to the forefront of the antifungal drug development industry, along with a few suggestions to overcome them, are considered.

Cutting-edge Bioinformatics strategies for synthesizing Cyclotriazadisulfonamide (CADA) analogs in next-Generation HIV therapies

Cyclotriazadisulfonamide (CADA) is a macrocyclic compound known for its unique mechanism in inhibiting HIV infection by downregulating the CD4 T-cell receptor, a crucial entry point for the virus. Unlike other antiretrovirals, CADA exhibits activity against a wide range of HIV strains, as all HIV variants require CD4 binding for infection. Furthermore, CADA has shown a synergistic effect with clinically approved anti-HIV drugs, offering potential for enhanced therapeutic strategies (Vermeire & Schols, [65]). One proposed mechanism for CADA’s inhibition of the CD4 receptor involves blocking the gates of the Sec61 channel, thereby preventing its translocation. However, CADA suffers from poor solubility and bioavailability. To address this, the study aimed to design CADA analogs with improved binding to the Sec61 channel, enhanced bioavailability, and reduced toxicity. The analogs were designed using SeeSAR, with Avogadro and Meeko used for 3D configuration and pseudoatom placement, respectively. AutoDock Vina version 1.2.4 was employed to predict the binding energies of these analogs. Of the 113 analogs designed, 93 demonstrated a more negative binding energy to the Sec61 channel compared to CADA. Structure-binding energy analyses were done to the top-binding analogs to show favorable structural modifications. Enzyme-ligand interactions were analyzed to elucidate the forces contributing to these binding energies. Additionally, 33 of the 113 analogs were deemed bioavailable using a bioavailability criteria specific for macrocycles. Toxicity predictions using PASS Online and StopTox identified analogs JGL023, JGL024, JGL032, and JGL047 as potential drug candidates. Molecular dynamics simulations using Gromacs-2020.4 revealed that JGL023 and JGL032 exhibited the most favorable binding to the Sec61 channel, as determined by evaluating ligand and residue flexibility, compactness, contact frequency, motion pathways, free energy, and other relevant parameters. Synthetic routes for these four analogs were proposed for future studies. The results of this study offer a new perspective on developing drugs to inhibit HIV entry.